This project will extend previous observations of the effects of histamine on mouse T lymphocyte-mediated cytolysis of allogeneic target cells. Histamine inhibits in vitro cytolysis and raises cyclic AMP levels by interaction with a histamine-type 2 receptor; the proportion of effector T lymphocytes bearing histamine receptors progressively increases during the immune response; the appearance of significant precentages of histamine receptor-bearing effector cells is associated with a fall in number of lytically active cells. Specific initial aims of the present project include (1) study of the interaction between histamine and other hormones, or drugs, especially beta-adrenergic drugs, prostaglandins, and cholinergic agonists; (2) isolation and characterization of immune lymphocyte populations enriched in, and depleted in, histamine receptor-bearing cells; (3) direct measurement of histamine receptors, by assay of binding of histamine to lymphocyte populations, and correlation of this binding to other histamine effects (inhibition of in vitro cytolysis, cyclic AMP changes). Further studies will assess the role of histamine and histamine receptor-bearing lymphocytes during in vitro induction of cytolytically active lymphocytes in mixed leucocyte cultures. Analysis of the in vivo effects of histamine include study of the relationship between tissue histamine content, and histidine decarboxylase activity, and the development of histamine receptors. The results of in vitro generation of cytolytic activity will be applied to analysis of the effect of histamine and histamine receptor-bearing cells on the in vivo generation of cytolytically active cells, especially in graft-versus-host reactions (injection of lymphocytes into x-irradiated allogeneic hosts), and in host-versus-graft immunization to allogeneic tumor cells and skin allografts. The information from these studies on histamine should help define the role of hormones in the control of T lymphocyte function.